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  1. Approach the newborn with ambiguous genitalia with sensitivity, avoiding use of ambiguous pronouns.

  2. Determine if there is a related life-threatening illness.

  3. Activate a multidisciplinary team to help establish a diagnosis and eventually the sex of rearing.




  1. Humans have bipotential embryologic tissues.

  2. Gender is differentiated by an orchestra of expression and interaction of specific genes and gene products.

  3. Chromosomes determine gonadal sex, but local factors influence differentiation of the internal and external genital structures.




46,XX Disorder of Sex Development (DSD) (Overvirilized Female)


  1. There are normal ovaries and Mullerian structures.

  2. Masculinization of the external genitalia occurs as a result of in utero exposure to androgens.

  3. Congenital adrenal hyperplasia (CAH) is most common and is potentially life threatening.

  4. 46,XX with testicular tissue

    1. Anomalous Y-to-X translocation, including the SRY gene during meiosis

    2. Ranges from ovotesticular DSD, to some degree of sexual ambiguity, to normal male phenotype


46,XY DSD (Undervirilized Male)


  1. Testes present

  2. Internal duct system or the external genitalia incompletely masculinized

  3. Phenotype is variable and can look like a normal female.

  4. Hypospadias, cryptorchidism, penoscrotal transposition, blind vaginal pouch

  5. Adrenal blocks potential causes of undervirilization

  6. Leydig cell failure or unresponsiveness to hCG and luteinizing hormone (LH)

    1. Decreased testosterone and/or dihydrotestosterone (DHT, seen with 5-alpha reductase deficiency) DHT

    2. No support of Wolffian ducts

    3. No support of external male genitalia

  7. Androgen insensitivity syndrome (AIS) or “testicular feminization”

    1. Can be partial

    2. Mutation of the steroid-binding domain of androgen receptor

    3. Testes present, but patient looks like a phenotypic female

  8. 5-α-Reductase deficiency

    1. Testosterone cannot be converted to DHT at target tissue.

    2. Patient is a normal male inside, but ambiguous on the outside.

    3. At puberty, testosterone increases significantly and masculinizes the external genitalia; this may be associated with a change in gender identity.

  9. Persistent Mullerian duct syndrome

    1. Abnormal anti-Mullerian hormone (AMH; formerly Mullerian Inhibitor Factor or Mullerian Inhibitory Substance) or its receptor occurs.

    2. Patient may look like a phenotypic male.

    3. This diagnosis is often made at the time of inguinal hernia repair or orchiopexy, when internal Mullerian structures (uterus, cervix, Fallopian tubes, upper two-thirds of vagina) are found.

  10. Congenital anorchia (“vanishing testes”)

    1. Loss of testes before 8 weeks’ gestation: female internally and externally with streak gonads

    2. At 8–10 weeks: ambiguous genitalia and variable duct formation

    3. At 12–14 weeks: male phenotype with anorchia

  11. Maternal ingestion of progesterone or estrogen or environmental hazards: pesticides, DES (diethylstilbestrol), OCPs (oral contraceptives), and in vitro fertilization (IVF) medicines all implicated

  12. Increased incidence of hypospadias in boys born through IVF


Chromosome DSD


  1. Klinefelter (XXY) and the 46,XY/47,XXY mosaic: usually not evident until adolescence

  2. Turner (XO) and the 45,XO/46,XX mosaic: streak gonads

  3. Can also have 46,XX and 46,XY with streak gonads


Ovotesticular DSD (Gonadal Dysgenesis)


  1. SRY (Sex determinng region Y) gene transposition (complete ...

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